GJA1 – Autosomal Dominant Palmoplantar Keratoderma and Congenital Alopecia

Keratoderma-hypotrichosis-leukonychia totalis syndrome (KHLS) is an extremely rare autosomal-dominant disorder characterized by severe palmoplantar hyperkeratosis, congenital alopecia and leukonychia totalis. Whole-exome sequencing in a pedigree with KHLS identified a heterozygous GJA1 missense variant c.23G>T (p.Gly8Val) that cosegregated with disease in two affected relatives and was also found de novo in an unrelated individual, consistent with autosomal-dominant inheritance and 3 probands (PMID:25168385).

GJA1 encodes connexin 43 (Cx43), a gap junction protein widely expressed in epidermis and hair follicles. The c.23G>T (p.Gly8Val) substitution lies in the N-terminal domain and does not impair plaque formation or dye coupling in HEK293 cells but confers a marked gain-of-function phenotype.

Functional assays employing Lucifer yellow microinjection, patch-clamp recording and calcium imaging demonstrated that Cx43 (p.Gly8Val) hemichannels exhibit significantly increased open probability at resting potential, resulting in enhanced Ca2+ influx. This aberrant hemichannel activity likely leads to cytoplasmic Ca2+ overload, keratinocyte apoptosis and subsequent hyperkeratosis.

No conflicting reports have been described to date, and the variant is absent from population databases, supporting pathogenicity. Clinical testing for GJA1 missense variants should include assessment of hemichannel function when interpreting novel alleles.

References

• Human Molecular Genetics • 2015 • Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome. PMID:25168385

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